Rerouted FSH and delaying ovarian aging

The National Institute of Child Health and Human Development awarded The Regents of the University of Colorado–Denver $615,431 on August 15, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to study follicle-stimulating hormone (FSH) actions in the ovary across the female lifespan.

The project investigates mechanisms by which rerouted FSH—redirected into the pulsatile secretory pathway via a carboxy-terminal heptapeptide sorting determinant—delays ovarian aging and enhances fertility in female mice. Prior work demonstrated that rerouted FSH-expressing female mice exhibit suppressed follicle atresia, increased egg production per cycle, and significantly delayed reproductive aging through at least 17 months of age. The research will employ multi-omics analysis to overlay gene, protein, and phosphoprotein expression signatures in ovaries of aged mice, identifying specific signaling networks regulated by each FSH signal input pattern. The project will test FSH secretion pattern recognition specificity through FSH receptor-mediated signaling and recruitment of distinct protein complexes, using epitope-tagged FSH receptors in granulosa cells. Pull-down experiments followed by mass spectrometry analysis of ovarian proteins will characterize the signaling mechanisms underlying enhanced follicular microenvironment and metabolic health.

Performance spans August 15, 2026, through May 31, 2031, at Aurora, Colorado. This is a project grant, an assistance type distinct from procurement contracting.

Abstract

The long-term goal of this project is to study the mechanisms of follicle-stimulating hormone (FSH) actions in the ovary across the female lifespan. Although the two pituitary gonadotropins (luteinizing hormone, LH and FSH) share a common -subunit (the -subunits are hormone-specific), their intracellular trafficking and secretion patterns in gonadotropes are distinct. LH is released in pulses via the regulated pathway, whereas FSH is constitutively secreted. Why this hormone-specific pattern has evolved and whether the target tissue, the ovary, senses gonadotropin-specific release pattern is not understood. Our in vivo studies identified that the carboxy terminus heptapeptide of LH is a gonadotrope-specific regulated sorting determinant. We redirected FSH using this sequence into the pulsatile LH secretory pathway and rescued fshb null mice. These rerouted FSH-expressing female mice demonstrate suppressed atresia resulting in vastly increased EGG production per cycle, and significantly delayed female reproductive aging as late as 17M of age. The central hypothesis is that rerouted FSH elicits distinct signaling events via FSH receptors in ovarian granulosa cells and establishes a conducive follicular microenvironment and better overall metabolic health, leading to enhanced female fertility and reproductive longevity. In aim 1, we will perform a multi-omics analysis by overlaying the gene, protein, and phosphoprotein expression signatures in ovaries of old age mice and identify specific signaling networks regulated by each FSH signal input pattern. Further, we will test how the FSH secretion pattern recognition specificity is achieved by fshr-mediated signaling and by recruitment of distinct protein complexes to activate different downstream gene/protein networks using n' MYC - tagged fshrs in granulosa cells. Pull-down experiments followed by mass spectrometry analysis of ovarian proteins will be performed. In aim 2, we will test how rerouted FSH provides a better microenvironment within the aging ovary. Molecular mapping of ovarian cell markers, age-specific changes in ovarian thickness using atomic force microscopy will be performed in mice across the lifespan. Ovarian follicles will be encapsulated in 3D hydrogels and cultured in vitro to monitor growth and functional characteristics. FSH signal inputs will be simulated using ovarian cells on microfluidics platform and the signaling readouts will be captured. In aim 3, we will investigate how rerouted FSH safeguards the overall metabolic health. Ovarian secretome will be analyzed by somascan arrays and bioid in vivo capture system and ovarian tissue metabolomics analysis will be performed. Fshr will be deleted in hepatocytes to determine if FSH directly acts on liver to maintain better overall metabolic health. Successful completion of our studies will lead to advancing the knowledge on how rerouted FSH signals to selectively recruit distinct fshr - CO-factor partner complexes and regulates fshr- mediated signal transduction pathways in ovaries across the life span. Collectively, our studies will provide novel therapeutic opportunities to extend fertility andfemale reproductive aging and overall health span.